Osteoarthritis, the most common form of arthritis, is a serious chronic disease that affects an estimated 51.9 million U.S. adults1 and 527.8 million adults globally.2 Osteoarthritis is the most prevalent joint disease and a leading source of chronic pain and disability in the United States.3,4  While often considered a disease of old age, an estimated 11.6 million U.S. adults suffering with osteoarthritis are of working age (20-64 years).5 Osteoarthritis may affect the knees, hips, hands, spine, or feet6; current estimates indicate that there are 24.7 million, 1 in 10 U.S. adults, with knee osteoarthritis.7

Those who live with osteoarthritis experience pain, stiffness, and swelling, which limits their function and mobility; these symptoms often impact osteoarthritis suffers in their daily lives. People living with osteoarthritis may experience a variety of symptoms; for some, pain is mild and occurs occasionally, while for others pain is severe and chronic. Regardless of where patients are in their osteoarthritis progression, their lives are impacted when everyday activities like walking a few blocks or going up and down stairs cause too much pain. In addition, many people with osteoarthritis are also diagnosed with other chronic conditions, such as heart disease, diabetes, and obesity; these comorbidities add to the burden that osteoarthritis sufferers manage.

While osteoarthritis is frequently described as a “wear and tear” disease, we understand it now as a disease of the whole joint, involving the cartilage, joint lining, ligaments, and bone.6 Characteristics of the disease include: degradation of tendons, ligaments and cartilage (the cushioning tissue between joints), bony changes of the joints, and inflammation of the joint lining (called the synovium).6 Palliative therapeutics compromise on efficacy, safety or durability. Currently, there are no approved treatments which alter the course of osteoarthritis; at Biosplice Therapeutics, we hope to change this with lorecivivint.

References

Lorecivivint (SM04690)

Overview

Biosplice Therapeutics has developed an injectable small-molecule inhibitor of the CDC2-like kinase (CLK) and dual-specificity tyrosine regulated kinase (DYRK) family.

Biosplice is conducting two large placebo-controlled phase 3 clinical trials where it hopes to demonstrate reduction in knee osteoarthritis pain with a single injection over the course of 6 months and 12 months, with follow-up beyond a year.

Based on the mechanism of action, Biosplice is also exploring the impact lorecivivint plays on inflammation, function, and cartilage protective effects through patient reported outcomes and structural endpoints.

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Mechanism of Action

Since its discovery in the early 1980s the Wnt pathway has increasingly been recognized as a critical cell signaling pathway that affects tissue health and homeostasis. Simply put, Wnt proteins interact with stem cells, which reside in all adult tissues, to orchestrate tissue remodelling.

Recently, increased understanding of cartilage growth mechanisms during osteoarthritis progression and aging has identified Wnt signaling to play a critical role in osteoarthritis pathogenesis, particularly cartilage and subchondral bone remodeling. Wnt pathway upregulation in diseased joints, which can occur through age, obesity, trauma or overuse, contributes to cartilage degeneration and osteoarthritis disease progression.

Through the selective inhibition of the kinases CLK2 and DYRK1A, lorecivivint downregulates downstream Wnt pathway proteins through alternative splicing. This decreases cartilage breakdown, which results in cartilage protective effects. Downregulation of the Wnt pathway also prompts mesenchymal stem cells to develop into chondrocytes, protecting and potentially replenishing the hyaline cartilage matrix. This, in turn, may lead to structural improvement and long-term pain benefit.

Lorecivivint potently inhibits the DYRK1A kinase, which leads to STAT3 inhibition, producing a powerful anti-inflammatory affect, resulting in both near-term pain relief and functional improvement.

Our novel mechanism of action is described in greater detail in our manuscript published by Osteoarthritis Research Society International’s Osteoarthritis and Cartilage journal.

In animal models, lorecivivint has demonstrated the ability to significantly inhibit inflammation and protect cartilage. This has produced both functional and pain improvement in numerous experiments.

The images below represent a cross section of a rat knee. The red staining represents the presence of hyaline cartilage. Both the control and treated groups received clipping of ligaments, which can erode cartilage over time. The control group (placebo-injected; represented on the left) experienced significant cartilage degradation. The treated group (lorecivivint-injected; represented on the right) showed significantly less cartilage damage over the placebo-injected group. The dose used represents the equivalent of 0.07mg in humans, the dose represented in our Phase 3 approval trials.

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Data to Date

Pain

In a Phase 2b study, lorecivivint demonstrated separation from placebo and statistically significant improvements in pain at multiple time points, with duration of response up to 24 weeks.

Function

In the same Phase 2b study, lorecivivint also demonstrated separation from placebo and statistically significant improvements in patient-reported function at multiple time points, with duration of response up to 24 weeks.

Safety and Bone Health

To date, more than 800 subjects have been treated with lorecivivint. Across all clinical trials, lorecivivint has appeared well tolerated with similar rates of adverse events compared to placebo and no evidence of systemic exposure. All SAEs observed were deemed unrelated to lorecivivint by investigators.

Structure and Cartilage

Based on the mechanism of action and cartilage protective effects in preclinical studies, Biosplice Therapeutics continues to investigate the full potential of lorecivivint in treating the whole joint by including structural endpoints in its Phase 3 trials.

As with animal studies, the protective and beneficial structural effects of lorecivivint on cartilage have indirectly been demonstrated in human clinical trials. Clinicians and practicing physicians treating osteoarthritis commonly use medial joint space width (mJSW) as a measure of joint health, as decreasing mJSW predicts knee replacement in clinical practice. In Biosplice’s Phase 2a trial, patients dosed with lorecivivint showed significant increases in mJSW at a year relative to placebo subjects (prespecified unilateral symptomatic subgroup). As the figure below demonstrates, these same patients also experienced significant improvements in pain at a year, demonstrating clinical benefit as well as structural improvements.

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Publications

Osteoarthritis and Cartilage | February 12, 2021

  • A Phase 2b Randomized Trial of Lorecivivint, a Novel Intra-articular CLK2/DYRK1A Inhibitor and Wnt Pathway Modulator for Knee Osteoarthritis

    Osteoarthritis and Cartilage. doi: 10.1016/j.joca.2021.02.004


    Yusuf Yazici, MD, Timothy E. McAlindon, MD, MPH, Allan Gibofsky, MD, JD, Nancy E. Lane, MD, Christian Lattermann, MD, Nebojsa Skrepnik, MD, PhD, Christopher J. Swearingen, PhD, Ismail Simsek, MD, Heli Ghandehari, MS, Anita DiFrancesco, BS, BA, Jamielle Gibbs, MPH, Jeyanesh Tambiah, MD, Marc C. Hochberg, MD, MPH

American College of Rheumatology (ACR) Convergence | November 02 - 05, 2020

Journal of Medical Economics | August 13, 2020

  • Health care resource utilization and burden of disease in a U.S. Medicare population with a principal diagnosis of osteoarthritis of the knee

    Journal of Medical Economics. doi: 10.1080/13696998.2020.1801453


    Fang Chen, Wenqing Su, Angela V. Bedenbaugh & Arman Oruc

Arthritis & Rheumatology | May 20, 2020

  • Lorecivivint, a Novel Intra‐articular CLK/DYRK1A Inhibitor and Wnt Pathway Modulator for Treatment of Knee Osteoarthritis: A Phase 2 Randomized Trial

    Arthritis & Rheumatology. doi: 10.1002/art.41315


    Yusuf Yazici, Timothy E. McAlindon, Allan Gibofsky, Nancy E. Lane, Daniel Clauw, Morgan Jones, John Bergfeld, Christopher J. Swearingen, Anita DiFrancesco, Ismail Simsek, Jeyanesh Tambiah, Marc C. Hochberg

Cartilage Regeneration & Joint Preservation Society (ICRS) World Congress | October 05 - 08, 2019

Cartilage Regeneration & Joint Preservation Society (ICRS) World Congress | October 05 - 08, 2019

Gordon Research Conference (GRC) - Wnt Signaling Networks in Development, Disease and Regeneration | August 11 - 16, 2019

Osteoarthritis and Cartilage | May 24, 2019

  • Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

    Osteoarthritis and Cartilage. doi: 10.1016/j.joca.2019.05.006


    V. Deshmukh, A.L. O'Green, C. Bossard, T. Seo, L. Lamangan, M. Ibanez, A. Ghias, C. Lai, L. Do, S. Cho, J. Cahiwat, K. Chiu, M. Pedraza, S. Anderson, R. Harris, L. Dellamary, S. KC, C. Barroga, B. Melchior, B. Tam, S. Kennedy, J. Tambiah, J. Hood, Y. Yazici

International Society for Pharmaeconomics and Outcomes Research (ISPOR) | May 18 - 22, 2019

International Cartilage Regeneration & Joint Preservation Society (ICRS) Summit | January 17 - 18, 2019

World Congress on Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases | April 19 - 22, 2018

World Congress on Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases | April 19 - 22, 2018

Osteoarthritis and Cartilage | September 15, 2017

Osteoarthritis and Cartilage | July 13, 2017

  • A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study

    Osteoarthritis and Cartilage, 25(10), 1598-1606. doi: 10.1016/j.joca.2017.07.006


    Y. Yazici, T.E. McAlindon, R. Fleischmann, A. Gibofsky, N.E. Lane, A.J. Kivitz, N. Skrepnik, E. Armas, C.J. Swearingen, A. DiFrancesco, J.R.S. Tambiah, J. Hood, M.C. Hochberg

International Cartilage Repair Society Heritage Summit | June 29 - July 01, 2017

International Society for Pharmacoeconomics and Outcomes (ISPOR) | May 20 - 24, 2017

Award Winning

Corporate Memberships and Collaborations

ORBIT Registry (Brigham and Women’s Hospital)

Biosplice Therapeutics is sponsoring the Osteoarthritis Registry of Biomarker and Imaging Trajectories (ORBIT). The data from this study will enhance our understanding of the natural history of knee osteoarthritis. This registry was developed in collaboration with investigators at Brigham and Women’s Hospital at Harvard Medical School.

PROGRESS OA (Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium)

Biosplice Therapeutics is a partner on the FNIH Biomarkers Consortium’s PROGRESS OA Project: Clinical Evaluation and Qualification of Osteoarthritis Biomarkers. The project seeks to qualify imaging and biochemical biomarkers with the FDA as prognostic biomarkers of disease progression in knee osteoarthritis.

Osteoarthritis Research Society International (OARSI)

Biosplice Therapeutics is proud to be a Corporate Member of OARSI, the leading medical society for advancing the understanding, early detection, treatment, and prevention of osteoarthritis through its exclusive dedication to research.  OARSI is the only organization that is exclusively dedicated to advancing osteoarthritis research.

International Cartilage Regeneration & Joint Preservation Society (ICRS)

Biosplice Therapeutics is proud to be a Corporate Member of the ICRS, the main forum for international collaboration in cartilaginous tissue research and joint preservation. The ICRS seeks to improve patients’ quality of life, decrease their disability, and reduce the impact of degenerative joint disease on healthcare systems worldwide.

STEpUP OA (Oxford University)

Biosplice Therapeutics is pleased to support Synovial fluid To define molecular EndotyPes by Unbiased Proteomics in OA (STEpUP OA), an Oxford University-led effort, which has created a partnership to characterize the synovial fluid protein signatures of osteoarthritis patients. Data generated as part of this endeavor may potentially guide clinical decision-making by allowing for better characterization of osteoarthritis disease stages and risk of progression.

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